Effect of ractopamine hydrochloride and zilpaterol hydrochloride on cardiac electrophysiologic and hematologic variables in finishing steers

Daniel A. Frese Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506.

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Christopher D. Reinhardt College of Veterinary Medicine, and the Department of Animal Science and Industry, College of Agriculture, Kansas State University, Manhattan, KS 66506.

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Steven J. Bartle Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506.

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David N. Rethorst Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506.

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Bhupinder Bawa Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506.

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Justin D. Thomason Department of Clinical Sciences, Kansas State University, Manhattan, KS 66506.

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Guy H. Loneragan Department of Animal and Food Sciences, College of Agricultural Sciences and Natural Resources, Texas Tech University, Lubbock, TX 79409.

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Daniel U. Thomson Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506.

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Abstract

OBJECTIVE To investigate the effects of dietary supplementation with the β-adrenoceptor agonists ractopamine hydrochloride and zilpaterol hydrochloride on ECG and clinicopathologic variables of finishing beef steers.

DESIGN Randomized controlled trial.

ANIMALS 30 Angus steers.

PROCEDURES Steers were grouped by body weight and randomly assigned to receive 1 of 3 diets for 23 days: a diet containing no additive (control diet) or a diet containing ractopamine hydrochloride (300 mg/steer/d) or zilpaterol hydrochloride (8.3 mg/kg [3.8 mg/lb] of feed on a dry-matter basis), beginning on day 0. Steers were instrumented with an ambulatory ECG monitor on days −2, 6, 13, and 23, and continuous recordings were obtained for 72, 24, 24, and 96 hours, respectively. At the time of instrumentation, blood samples were obtained for CBC and serum biochemical and blood lactate analysis. Electrocardiographic recordings were evaluated for mean heart rate and arrhythmia rates.

RESULTS Steers fed zilpaterol or ractopamine had greater mean heart rates than those fed the control diet. Mean heart rates were within reference limits for all steers, with the exception of those in the ractopamine group on day 14, in which mean heart rate was high. No differences in arrhythmia rates were identified among the groups, nor were any differences identified when arrhythmias were classified as single, paired, or multiple (> 2) beats.

CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that dietary supplementation of cattle with ractopamine or zilpaterol at FDA-approved doses had no effect on arrhythmia rates but caused an increase in heart rate that remained within reference limits.

Abstract

OBJECTIVE To investigate the effects of dietary supplementation with the β-adrenoceptor agonists ractopamine hydrochloride and zilpaterol hydrochloride on ECG and clinicopathologic variables of finishing beef steers.

DESIGN Randomized controlled trial.

ANIMALS 30 Angus steers.

PROCEDURES Steers were grouped by body weight and randomly assigned to receive 1 of 3 diets for 23 days: a diet containing no additive (control diet) or a diet containing ractopamine hydrochloride (300 mg/steer/d) or zilpaterol hydrochloride (8.3 mg/kg [3.8 mg/lb] of feed on a dry-matter basis), beginning on day 0. Steers were instrumented with an ambulatory ECG monitor on days −2, 6, 13, and 23, and continuous recordings were obtained for 72, 24, 24, and 96 hours, respectively. At the time of instrumentation, blood samples were obtained for CBC and serum biochemical and blood lactate analysis. Electrocardiographic recordings were evaluated for mean heart rate and arrhythmia rates.

RESULTS Steers fed zilpaterol or ractopamine had greater mean heart rates than those fed the control diet. Mean heart rates were within reference limits for all steers, with the exception of those in the ractopamine group on day 14, in which mean heart rate was high. No differences in arrhythmia rates were identified among the groups, nor were any differences identified when arrhythmias were classified as single, paired, or multiple (> 2) beats.

CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that dietary supplementation of cattle with ractopamine or zilpaterol at FDA-approved doses had no effect on arrhythmia rates but caused an increase in heart rate that remained within reference limits.

Supplementation of feed with the βAAs ractopamine hydrochloride and zilpaterol hydrochloride during the last 20 to 42 days of the feeding period has been used extensively in the cattle industry to improve weight gain and feed efficiency since the FDA approved this use in 2003 and 2006, respectively.1,2 Use of ractopamine and zilpaterol in cattle results in an increase in ADG, gain-to-feed ratio, and carcass weight and decrease in DM feed intake, thereby greatly increasing efficiency at the end of the feeding period.3–5

In human medicine, βAAs have been used widely for decades for treatment of respiratory ailments such as asthma because of their bronchodilatory effects. However, physiologic responses to βAAs are not limited to the respiratory tract because βAA receptors exist on nearly every mammalian cell, resulting in wide-ranging effects that include vasodilation, bronchodilation, smooth muscle relaxation, and positive inotropic effects.6

Despite their documented benefits, these pharmaceuticals have been associated with occasional adverse drug events. Long-term use has been associated with an increase in the mortality rate of humans with asthma.7 Myocardial toxic effects, myocardial apoptosis, and an increase in the risk of death in humans and other species have been linked to βAAs.8–11 Cardiac effects commonly associated with administration of short-acting βAAs include tachycardia, tremors, a decrease in serum potassium concentration, and an increase in blood glucose concentration.12 The role of βAAs in producing ECG arrhythmias varies. In 1 study13 involving humans, ventricular arrhythmias were associated with fenoterol but not albuterol administration. Another study14 involving children revealed no differences attributable to βAAs in Holter monitor recordings.

Physiologic responses to βAAs vary by dose, drug, and species to which they are administered. For example, ractopamine fed to Greyhounds at a dose of 1 mg/kg (0.45 mg/lb; approx twice the dose commonly fed to cattle) reportedly has multiple adverse cardiological effects, including VPCs, SVPCs, and multiform VPCs as well as extensive regions of necrosis of the ventricular walls.15 However, these effects have not been identified in cattle.2

Both ractopamine and zilpaterol have been reported to increase the risk of death of feedlot cattle during the late feeding period by 91% and 75%, respectively.16 In the associated study,16 cattle that were shipped to the abattoir during the months of June through September were at higher risk of death than those shipped during other periods, indicating that seasonal factors such as high ambient temperature may be a risk factor for death as well.16

These reports, combined with the documented effects of βAAs on cardiac function in species other than cattle, suggest that βAAs may have electrophysiological effects on feedlot cattle. Data are limited regarding the cardiac and electrophysiologic effects of ractopamine and zilpaterol in finishing cattle. Therefore, the purpose of the study reported here was to determine the effects of ractopamine and zilpaterol on clinicopathologic variables and ambulatory ECG recordings of finishing beef steers.

Materials and Methods

Cattle

Forty Angus steers (mean ± SEM body weight, 506 ± 6 kg [1,012 ± 13 lb]) were acquired from a commercial feeding facility (a single ranch) in southwest Kansas. Steers were selected from a larger group on the basis of uniformity of body weight and condition and had been adapted to a standard commercial finishing diet prior to shipment.

On arrival, steers were individually weighed and their identification recorded. They were then moved to a pen and provided free access to grass hay and fresh water. Each steer received 3.7 kg (8.1 lb) of a finishing diet, primarily consisting of corn and distiller's grains, with a formulated net energy for maintenance of 2.12 Mcal/kg (0.96 Mcal/lb) and net energy for gain of 1.45 Mcal/kg (0.66 Mcal/lb). Steers were allowed to readapt to the finishing diet over 10 days. After 10 days, steers were moved into 6 dirt-floor pens with individually electronically gated feed bunks.a All feed bunk gates were locked open and the cattle were provided free access to feed on a pen basis. The Kansas State University Institutional Animal Care and Use Committee approved all study protocols for animal handling and care (approval No. 3250).

Allocation protocol

On day −43, steers were weighed, and 30 steers were selected on the basis of their calm temperament and previously observed use of the feed bunk gates. The 6 heaviest steers within this selected group were identified and randomly assigned to 1 of 6 treatment-pen-block combinations. The 6 remaining heaviest steers were then randomly assigned in a similar manner, and this process was continued until all steers were assigned to a treatment-pen-block combination (10 steers/treatment; 5 steers/block). This method of stratification was used to limit variation attributable to factors such as environmental temperature and feed consumption that might have unequally affected steers of different body weights.

Calves within pens were grouped into 2 blocks (representing timing of treatment initiation), with treatments equally distributed between blocks. Pens consisted of 6 outdoor dirt-floor pens approximately 18 × 3.6 m in size, with 5 individual feeding gates in each pen. Feedbunk electronic gate keys were placed around the neck of each steer by use of a heavy-duty plastic chain. Each steer was provided approximately 2.5 m2 of shade. Free access to water was provided from a tank located at the rear of the pen. Steers were allowed 43 days of feedbunk gate training to allow them time to adapt and operate the individually gated feedbunks.

Diets

Three types of diet were used in the study: base feed alone (control diet), base feed supplemented with zilpaterol hydrochlorideb (8.3 mg/kg [3.8 mg/lb] of feed on a DM basis), and base feed supplemented with ractopamine hydrochloridec (300 mg/steer/d). The control diet contained a higher roughage content than most commercial feedlot diets, and this diet was selected as a precaution because of the frequent handling and disruptions to cattle routine during the study.

The βAAs were mixed into the base feed. Diets containing ractopamine were mixed in batches from the control diet by adding 320 g of a type B ractopamine hydrochloride medicated article (4,410 g/metric ton on an air-dry basis) to 36.3 kg (80 lb) of control diet on an as-fed basis, which provided 300 mg of ractopamine in 7.25 kg (16 lb) of diet on an as-fed basis. Diets were mixed for 5 minutes in a ribbon mixer. Target drug concentration was verified by extracting 4 samples from a batch of feed and pooling them into a single sample, freezing those samples, and then submitting them to a commercial laboratory for analysis. The dose of ractopamine used in the study is a commonly fed dose for finishing cattle in commercial feedlots and consistent with FDA-approved label instructions. Diets containing zilpaterol were mixed in an identical manner, with 514 g of a type B zilpaterol hydrochloride medicated article (480 g/ton) for a target diet concentration of 8.3 mg/kg on a DM basis in accordance with the FDA-approved label instructions.

For both βAA-supplemented diets, 3 to 4 days’ worth of diet were batched per mixing and stored until used. The mixer was flushed between batches that contained different treatments by use of compressed air followed by mixing of 4.5 kg (10 lb) of control diet for 5 minutes, and this process was repeated once. Random samples of the second batch of diet used in the flush process were obtained, and both diet batches were discarded. The obtained samples were submitted to the commercial laboratory to verify absence of ractopamine and zilpaterol in the feed after flushing.

Treatment protocol

Treatment was initiated on study day 0, and day 0 for each block within a pen was separated by 5 calendar days. Steers were fed their assigned diet individually and were fed twice daily, with the diet first delivered at 7:00 am and again between 9:00 am and 10:00 am. Daily feed amount was individually determined by visual estimation of feed remaining from the prior days’ feed delivery. Remaining feed was not discarded and remained in the feed bunk.

On days 12 and 7 for blocks 1 and 2, respectively, the feeding protocol was changed and all residual feed was removed from bunks and weighed before being discarded. Starting on these days, steers in the ractopamine group were fed 7.25 kg of diet (containing 300 mg of ractopamine) on an as-fed basis in the first feeding and then were fed control diet only in the second feeding. Cattle that received the control diet or the zilpaterol-supplemented diet were fed their assigned diet at both feedings. The final day for feeding zilpaterol was day 24 to conform with the FDA-specified withdrawal period for this drug. Water consumption within each pen was recorded daily by filling each tank to a designated level and recording the volume of water added with a water meter.

Blood sample collection and analysis

On days −16, −11, 6, 13, and 23, cattle were individually restrained in a commercial hydraulic chute and weighed. Blood samples for CBC and serum biochemical analysis were collected via jugular venipuncture into a 60-mL disposable syringe.d Baseline blood samples for CBC and serum biochemical analysis were collected from all steers in blocks 1 and 2 on days −11 and −16, respectively. Collected blood was immediately transferred through the rubber stopper into three 10-mL serum collection tubes (serum biochemical analysis) and one 6-mL EDTA tubee (CBC). Blood samples for measurement of blood lactate concentration were collected on days −2, 1, 6, 13, and 23. On days −2 and 1, these samples were collected into a 6-mL collection tube containing sodium heparin. On days 6, 13, and 23, these samples were collected in an identical manner as described for samples for serum biochemical analysis. Following collection, all blood samples were stored in chilled coolers prior to centrifugation at 3,000 × g for 15 minutes.

All samples were processed within 3 hours after collection. Serum was separated immediately after centrifugation and stored overnight at 4° to 6°C. Blood and serum samples were then submitted to the Kansas State University Veterinary Diagnostic Laboratory for serum biochemicalf and blood lactateg analyses. Complete blood counts were performed by use of a hematology analyzer,h except for blood samples obtained from block 1 on day 6, which were submitted to the Kansas State University Veterinary Diagnostic Laboratory for analysisi because the hematology analyzer was unavailable for use on that day. Laboratory personnel were blinded to treatment group assignment.

Instrumentation of steers

At the same points that blood samples were collected, steers were instrumented with a commercially available ambulatory digital ECG (Holter) recorder.j The unit involved 5 lead wires and 3 recording channels for data collection redundancy. A silver–silver chloride electrodek was applied to each of 5 vertically aligned anatomic sites just caudal to the forelimbs: 3 to 5 cm dorsal to the level of the olecranon (left and right sides, location 1), at the level of the dorsal edge of the scapula (left and right sides, location 2), and at the dorsal midline. In preparation for this, application sites were shaved of hair with a No. 40 blade and wiped with 99% isopropyl alcohol–soaked 4 × 4-inch gauze sponges. An oil-based calcium soapl was applied to the center sponge, and cyanoacrylate glue was applied continuously to the outer edge of the electrode prior to placement on the prepared site. The color-coded lead harness was attached with the following lead locations: black, left side location 1; brown, left side location 2; red, dorsal midline; white, right side location 2; and green, right side location 1.

Lead wires were snapped onto the electrode and securely attached to each electrode by means of a 2.5 × 1-cm section of adhesive tape across the lead attachment to either edge of the electrode base, avoiding contact with the steer itself. A custom-made 5-cm-wide elastic girth strap with a hook-and-loop fastener was then placed over all electrodes and wires, with the lead wire harness extending cranially at the dorsal midline. The elastic girth was secured on each steer by encircling the steer twice with 10-cm-wide elastic bandage tapem overlapping the cranial and caudal edges of the elastic girth.

A custom harness made of polyester webbing was then applied to each steer. This harness consisted of a 10-cm-wide girth strap with shoulder straps that attached to the girth strap, crossing between the forelimbs and again over the dorsal aspect of the neck cranial to the point of the shoulder. A crupper strap was looped under the tail, placed along the dorsal midline, and attached to the girth strap. A canvas pouch attached to the dorsal aspect of the harness contained the Holter monitor in a protective container with the lead harness inserted through the protective box into the monitor (Figure 1).

Figure 1—
Figure 1—

Photograph showing a steer fitted with a Holter monitor and harness.

Citation: Journal of the American Veterinary Medical Association 249, 6; 10.2460/javma.249.6.668

Steer identification number was entered into the Holter monitor, and the ECG signal was checked prior to release of each steer from the chute. Each Holter monitor was also assigned its own unique number independent of steer identification. This identification was subsequently assigned to all data files for an individual recording until analysis was complete to maintain blinding. The Holter monitor continuously recorded the ECG data onto a secure digital data card. Harnesses with monitors were applied between 4:00 pm and 7:30 pm on days −2, 6, 13, and 23 and removed between 4:00 pm and 7:00 pm on days 1, 7, 14, and 26. Electrocardiographic data were collected throughout days −2 to 1, 6, 7, 13, 14, and 23 through 26. Steers with Holter units requiring maintenance during the recording period were removed from their home pen and restrained in a hydraulic chute so that necessary maintenance could be performed.

The Holter data file was transferred from the secure digital data card into a commercially available analysis program.n The software identified individual heartbeats as normal, abnormal, or artifact. Each recording was analyzed in its entirety by a board-certified veterinary cardiologist who was blinded to treatment assignment. Heartbeats identified as abnormal were individually classified for subsequent statistical analysis. After data evaluation, output results were compiled in hourly intervals. Heart rate was determined by measurement of R-R interval duration. Mean heart rate was reported by the software as the mean of all R-R intervals not having a declared artifact within an hour.

Electrocardiogram arrhythmia events were summarized within steer into 24-hour intervals by setting hour 0 of the day to 7:00 am to pair the time of morning feeding with beginning of a treatment day. An arrhythmia event was defined as any ECG rhythm in which not all P waves and QRS-T complexes were unremarkable. Arrhythmias were reported as total count of events for each hour of each classification and then summarized by treatment day. Arrhythmia events were classified as SVPC or VPC in origin and as single beat, paired beat, or multiple (> 2) beat. Data recorded at times associated with steer handling (ie, prior to 7:00 pm on day of monitor application and after 4:00 pm on day of monitor removal) were not included in the analysis.

On day 27, steers were transported to a commercial abattoir in southwest Kansas for slaughter. The entire heart, lungs, and liver were collected from each steer after slaughter and placed in preidentified containers for each steer. All organs were visually examined for grossly evident lesions. Subsamples of each organ were immediately prepared. For the heart, a 1-cm cross section was obtained through both ventricles and the septum halfway between the base and apex. For the lungs, a 200- to 400-g specimen was obtained from a caudal lung lobe. For the liver, a 200- to 400-g specimen was obtained. Heart, lung, and liver specimens were placed in sealed plastic bags that were transferred to ice-cooled containers for transportation to the laboratory.

For histologic analysis, tissue specimens were reduced in size to approximately 1 to 2 cm3 and placed in containers with 10% formalin solution. Formalin-fixed, paraffin-embedded specimens were then prepared and analyzed by a board-certified veterinary pathologist who was blinded to treatment assignment. To identify apoptotic cell death, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling stainingo was performed in accordance with the manufacturer's instructions on heart tissue sections from all the treatment groups, with canine testis and lymph node specimens used as positive control specimens. For this analysis, formalin-fixed, paraffin-embedded specimens were sectioned onto positively charged slides and heated for 25 minutes at 60°C. Sections were pretreated with proteinase K (20 μg/μL) for 15 minutes at room temperature (approx 21°C) and 3% peroxide for 5 minutes. Slides were incubated in working-strength stop-wash buffer for 10 minutes at room temperature to prevent nonspecific calcium binding and then incubated with working-strength terminal deoxynucleotidyl transferase enzyme (1:50) for 1 hour at 37°C. Then, α-digoxigenin conjugate was added for 30 minutes at room temperature, and sections were stained with diaminobenzidine and counterstained with hematoxylin.

Statistical analysis

For the primary variables of interest (heart rate and arrhythmias), a sample size of 10 experimental units (steers)/treatment group was calculated as being able to detect a 12.5% difference between treatment and control groups. Assumptions for calculation included a 10% coefficient of variation, an α value of 0.05, and a β value of 0.20.

Summary statistics were calculated and are reported as mean and 95% CI or SEM. All data were analyzed by means of a generalized linear mixed model procedure and statistical software,p accounting for repeated measures when appropriate and including the fixed effects of treatment, treatment day, and their interaction. Block and pen were included as random effects. Degrees of freedom were calculated by use of the Kenward-Rogers method. The repeated-measure covariance structure and distribution type were chosen to fit the statistics and variable tested by assessment of the Akaike information criterion. Arrhythmia classifications were analyzed as a negative binomial distribution, with data transformed by adding 1 to the total count for each category of arrhythmia. The natural logarithm of readable recording hours within treatment day was used as an offset so results would be adjusted to a 24-hour period. Values of P < 0.05 were considered significant for all statistical tests.

Mean heart rate was analyzed by consideration of the hourly heart rate as a subsample within treatment day, with random effects of block and repeated measures by steer. Hour intervals with < 100 readable heart beats were removed from the dataset and treated as missing data. Holter recordings for days 6 to 7 and days 13 to 14 were recorded and analyzed as a single 24-hour period and labeled day 7 and day 14, respectively.

Performance data were calculated by use of body weights from days −2 and 26. Body weight on day 26 was reduced by 3% for calculation of final body weight, ADG, gain-to-feed ratio, and dressing percentage. Carcass identification was maintained at the commercial abattoir by matching the visual identification tag of each steer to order of slaughter and the carcass identification number of each steer assigned by the abattoir. Water consumption per steer was calculated as the total liters delivered daily divided by the number of steers in the pen on that day.

Results

Cattle

Three steers (2 from the control group and 1 from the zilpaterol group) were replaced during training because of failure to learn to operate the feed bunk gate and eat without assistance. Each of these steers was replaced at the time of random allocation to treatment groups with a steer from the pool of unallocated steers that was nearest to it in body weight, resulting again in 10 steers in each treatment group. Two of the 5 steers in block 2 of the zilpaterol group had Holter data files on day −2 that were invalid and not recoverable; therefore, the 2 steers were omitted from analyses involving Holter data, leaving 8 steers in the zilpaterol group overall. One steer in the control group was removed on day 14 of the study for severe pododermatitis unrelated to the study, and all data collected from this steer were excluded from all analyses, leaving 9 steers in the control group overall.

Effects of treatment

Steers in the ractopamine group had significantly higher hot carcass weights and final live body weights than did steers in the control group (Table 1), but these values did not differ significantly from those of steers in the zilpaterol group. No significant differences were identified among treatment groups with regard to ADG, gain-to-feed ratio, dressing percentage, longissimus muscle area, fat thickness at the 12th rib, yield grade, or marbling score. A treatment-by-week interaction was identified for feed intake, whereby feed intake in weeks 2 and 3 was greater in the ractopamine group than in both the zilpaterol and control groups. Feed intake in the ractopamine group was greater in week 2 than in week 1 and less in weeks 3 and 4 than in weeks 1 or 2. Feed intake in the control group was less in weeks 3 and 4 than in weeks 1 and 2. Feed intake in the zilpaterol group was less each successive week. No differences were detected in daily water consumption among the control (mean ± SEM, 45.1 ± 6.3 L/steer/d), zilpaterol (45.4 ± 6.3 L/steer/d), and ractopamine (46.8 ± 6.5 L/steer/d) groups.

Table 1—

Performance and carcass characteristics as well as DM intake of finishing steers fed a control diet (n = 10) or the control diet plus zilpaterol hydrochloride (8.3 mg/kg [3.8 mg/lb] of feed on a DM basis; 10) or ractopamine hydrochloride (300 mg/steer/d; 10) for 24 days.

 ControlZilpaterolRactopamine
VariableMeanSEMMeanSEMMeanSEM
Performance characteristics
   Initial body weight (kg)581a8.7583a8.3599a8.3
   Final body weight (kg)616a11.3637a,b10.7652b10.7
   ADG (kg)1.27a0.231.91a0.231.90a0.23
   Gain-to-feed ratio0.13a0.020.19a0.020.18a0.02
   Hot carcass weight (kg)377a7.3390a,b7.0398b7.0
   Dressing percentage63.8a0.0163.9a0.0163.7a0.01
Carcass characteristics
   Longissimus muscle area (cm2)85.8a4.787.1a4.694.9a4.6
   Back fat (cm)1.18a0.121.10a0.121.09a0.12
   Yield grade3.17a0.313.03a0.312.62a0.31
   Marbling score521a29.4531a27.9535a27.9
DM intake (kg)
   Week 110.0a,A0.3410.6a,A0.3310.6a,A0.33
   Week 29.9a,A0.3410.0a,B0.3411.2b,B0.33
   Week 38.7a,B0.349.4a,C0.3410.0b,C0.33
   Week 49.1a,B0.359.1a,D0.3410.0a,C0.34

Within a row, values with different superscript lowercase letters differ significantly (P < 0.05).

Within a column, values with different superscript uppercase letters differ significantly (P < 0.05).

To convert kilograms to pounds, multiply by 2.2.

Creatine kinase activity on days 13 and 23 was significantly higher in the zilpaterol group than in the other 2 groups (Table 2). No differences in blood lactate concentration were detected among treatment groups, nor were any differences identified among groups with respect to serum biochemical values (Table 3).

Table 2—

Blood lactate concentration and creatine kinase activity on various study days (with day 0 as time of first treatment) for the finishing steers represented in Table 1.

 ControlZilpaterolRactopamine
Variable, by dayMean95% CIMean95% CIMean95% CI
Lactate (mmol/L)*
   Day −23.62.2–5.94.72.8–7.73.72.2–6.1
   Day 13.11.9–5.14.32.6–7.04.22.5–6.8
   Day 62.61.6–4.21.81.1–2.92.01.2–3.4
   Day 134.22.5–7.12.81.7–4.83.52.1–5.8
   Day 232.41.5–4.01.71.0–2.71.81.1–2.9
Creatine kinase (U/L)*
   Day −11 or −16258a,A172–388182a,A122–270189a,A127–282
   Day 6171a,B114–257196a,A131–291148a,A99–220
   Day 13111a,C74–167220b,A147–327120a,A81–178
   Day 23132a,B,C88–198226b,A152–337135a,A152–337

The reference range of the Kansas State University Veterinary Diagnostic Laboratory for serum creatine phosphokinase activity is 159 to 332 U/L. That for blood lactate concentration has not been established.

See Table 1 for remainder of key.

Table 3—

Summarized results of selected serum biochemical analyses for all measurement points for the finishing steers represented in Table 1.

  ControlZilpaterolRactopamine 
VariableReference range*Mean95% CIMean95% CIMean95% CIP value
Glucose (mg/dL)29–7367.954.8–81.164.850.8–78.868.254.3–82.10.53
BUN (mg/dL)9–2410.36.8–15.88.55.6–12.910.06.7–15.30.58
Creatinine (mg/dL)0.5–1.61.201.12–1.301.301.22–1.391.241.16–1.330.29
Sodium (mmol/L)131–155143141–144142141–143143141–1430.26
Potassium (mmol/L)4.2–6.34.754.60–4.914.864.71–5.014.84.65–4.940.59
Chloride (mmol/L)92–11798.597.5–99.597.597.5–98.598.597.5–99.50.39
Bicarbonate (mmol/L)21–3125.423.5–27.325.423.4–27.324.622.6–26.60.63

Values represent reference ranges of the Kansas State University Veterinary Diagnostic Laboratory.

P values represent the main effect of treatment. Values of P < 0.05 were considered significant. No interactions with sample collection point or treatment were detected.

See Table 1 for remainder of key.

The mean percentage of the Holter data recording period for each steer during each 24-hour collection period that provided readable ECGs was 69% (SD, 24.4%). The most common cause of artifact data was steer activity such as walking and feeding. The zilpaterol and ractopamine groups had greater mean heart rates than did the control group. Treatment, day, and treatment-by-day interaction had a significant effect on heart rate. On day −1, mean heart rate was statistically similar among the control (71.7 ± 5.3 beats/min), zilpaterol (68.9 ± 5.9 beats/min), and ractopamine (67.4 ± 5.3 beats/min) groups. The zilpaterol group had a higher mean heart rate than did the control group on days 7, 14, and 23 but not on days 0, 24, and 25. The ractopamine group had a higher mean heart rate than did the control group on days 7, 14, and 24 but not on days 0, 23, or 25 (Table 4). Mean heart rate was lower in the control group on day 4, compared with that on day 0, but was not lower when compared with that on days 14, 23, 24, and 25.

Table 4—

Mean heart rate (beats/min) at various points for the finishing steers represented in Table 1.

 ControlZilpaterolRactopamine
Study dayMeanSEMMeanSEMMeanSEM
084.0a,A5.677.8a,A,B6.373.3a,A,B5.6
766.8a,A,B,C,D3.680.9b,A,B3.582.3b,A3.5
1472.3a,A,C,D4.579.6a,b,A,B3.585.1b,A3.9
2371.3a,B,C1.376.3b,A,B1.474.7a,b,A,B1.5
2473.5a,A,C1.574.6a,A1.479.9b,A1.4
2577.5a,A,D1.579.4a,B1.577.3a,A,B1.4

See Table 1 for key.

No differences (P > 0.20) in number of arrhythmia events per day for VPCs or SVPC or in beats per event were detected among treatment groups (Tables 5 and 6). Single-beat arrhythmias accounted for 84.0% (242/288) of all arrhythmia events, paired-beat arrhythmias accounted for 11.1% (32/288), and multiple-beat arrhythmias accounted for 4.9% (14/288). Notably, however, 75.3% of all arrhythmia events were detected in 1 steer in the ractopamine group, which had 72.3% (175/242) of all single-beat arrythmias, 90.6% (29/32) of all paired-beat arrhythmias, and 92.8% (13/14) of all multiple-beat arrhythmias.

Table 5—

Number of ventricular arrhythmia events per steer per day for the finishing steers represented in Table 1.

 ControlZilpaterolRactopamine
VariableMean95% CIMean95% CIMean95% CI
Total ventricular arrhythmias20–1961.50–1894.90–787
Single arrhythmia1.80–3,7071.80–3,3954.50–5,204
Paired arrhythmias1.71.3–2.21.81.3–2.32.01.5–2.6
> 2 arrhythmias1.71.3–∞1.71.3–∞1.71.3–∞

Means presented within each row represent an independent statistical model. Means should not be compared across rows.

See Table 1 for remainder of key.

Table 6—

Number of supraventricular arrhythmia events per steer per day for the finishing steers represented in Table l.

 ControlZilpaterolRactopamine
VariableMean95% CIMean95% CIMean95% CI
Total supraventricular arrhythmias35.88.6–148.240.99.5–175.532.57.2–108.8
Single arrhythmia30.58.1–115.135.28.9–138.4280–5,204
Paired arrhythmias3.51.8–6.64.22.2–7.63.92.1–7.3
> 2 arrhythmias3.42.5–4.63.42.5–4.52.82.1–3.8

See Tables 1 and 5 for remainder of key.

No significant histologic lesions were detected in specimens of lung, liver, or heart tissue from steers in any treatment group. However, mild myocardial degeneration and infiltration by small numbers of lymphocytes and plasma cells were identified in liver, kidney, and heart specimens from some steers in each group. No terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling–positive cells (which would have indicated apoptosis) were identified in any steer.

Discussion

To the authors’ knowledge, the study reported here represented the first in which a Holter monitoring system was used for continuous ambulatory ECG recording over multiple days in cattle and the first in which the effects of βAAs on those readings were evaluated. Previous studies17,18,q in which ECG monitoring of cattle has been performed have involved recording durations of minutes to a few hours and in a restrained environment of a clinical hospital setting. No studies in natural settings have been performed to examine the prevalence of arrhythmias or the cardiac effects of βAAs in cattle.

The effects of βAAs on feed intake, growth performance, and carcass characteristics of the finishing steers of the present study were generally in accord with previously reported effects of ractopamine and zilpaterol.19,20 Supplementation of feed with zilpaterol or ractopamine increased ADG by approximately 0.6 kg (1.3 lb), or 47%; however, this effect was not significant. Because the present study was not designed specifically to evaluate effects on performance, the failure of performance characteristics to be significantly affected should be interpreted accordingly.

Resting heart rate for healthy cattle ranges from 49 to 84 beats/min.21 Cattle fed zilpaterol or ractopamine had greater mean heart rate than did cattle fed the control diet alone, but mean heart rates for all treatment groups were within reference limits except for steers in the ractopamine group on day 14. The magnitude of the mean heart rate difference between the zilpaterol (14.1 beats/min) or ractopamine (15.5 beats/min) group and the control group was greatest on day 7 and decreased as the feeding period progressed until no differences were detected on the final treatment day (Table 4). This could have been attributable to desensitization of the steers to βAA, which has been reported to occur.22 The reason for the lower mean heart rate on day 7 for steers fed a βAA was not readily apparent. The increase in mean heart rate with ingestion of zilpaterol or ractopamine was consistent with findings in previous reports of cattle fed zilpaterol1 or ractopamine.23 The magnitude of the increase in mean heart rate in cattle fed zilpaterol at a dose of approximately 0.14 mg/kg (0.06 mg/lb) was much lower than that reported for horses fed zilpaterol at 0.17 mg/kg (0.08 mg/lb), in which severe tachycardia was identified.24,25 However, the increase in mean heart rate of steers fed zilpaterol or ractopamine was somewhat greater than the increase of 9.1 beats/min identified in a meta-analysis of single-dose βAA administration in humans.9

Supraventricular arrhythmias are reportedly more common than ventricular arrhythmias in cattle,17 which is consistent with the results of the present study. However, the prevalence of supraventricular arrhythmias in cattle is lower than in horses, in which supraventricular arrhythmias are common.18 Atrial fibrillation is a commonly reported arrhythmia of cattle,17 and other supraventricular arrhythmias are reported rarely for this species.1,2 The rates of SVPC identified in the present study were higher than those in previous reports but were also more broadly defined to include more events than a single type of arrhythmia.17 In a previous study,q the most common clinical disorder in cattle with subsequently diagnosed atrial fibrillation was gastrointestinal disorder and conversion back to a normal sinus rhythm without specific treatment (60% affected). In the present study, several instances of second-degree atrioventricular block were identified, which is rare in cattle but common in horses. Other benign events such as bradycardia have been reported for cattle from which food was withheld prior to surgery.26

Ventricular arrhythmia rates in the present study (1.5 to 4.9 events/d) were below VPC rates (> 3.0 VPCs/h), and VPCs have been shown to increase the risk of death in humans.27 Additionally, healthy humans with VPC rates > 30 VPCs/h have an increased risk of death due to cardiovascular disease and myocardial infarction specifically, relative to the risk for those without such high rates.28 However, care should be taken in extrapolation of human health hazard thresholds to other species because the risks of such events in veterinary species are not well defined. Extrapolation of the results of the present study to the health hazards of βAAs for cattle should be done with caution given that this was not a health risk assessment study. It should also be noted that the gross and histopathologic myocardial damage identified in Greyhounds after βAA administration15 was not identified in the study steers at necropsy.

The high proportion (75.3%) of arrhythmias detected in 1 steer in the present study warrants further investigation. Although this steer was in the ractopamine group, no inferences should be drawn as to the influence of ractopamine on its arrhythmia rate given that this rate was higher than that of all other steers on all measurement days throughout the study period.

Blood lactate concentrations in the present study were in the general range of or slightly higher than previously reported values for finishing steers (1 to 2 mmol/L).29 Blood creatine phosphokinase concentrations were higher on days 13 and 23 in the zilpaterol group than in the other groups, consistent with other reported findings.1 However, all such values were within reference limits. An increase in blood creatine phosphokinase concentration has been associated with many factors, including myocardial infarction and damage of skeletal muscle.30 The increase detected in the present study may have been attributable to an increase in lean body mass, which reportedly occurs in humans or cattle (as identified through a decrease in USDA yield grade).18,30,31 However, other possible factors underlying an increase in blood creatine phosphokinase concentration include mild muscle damage, and such other factors cannot be ruled out as a potential source. High blood creatine phosphokinase concentration in humans can be an indicator of myocardial infarction; however, this association can be misinterpreted in humans with acute myocardial infarction and high lean body mass.30

Although no differences in arrhythmia rates or classification were identified among treatment groups in the present study, this did not rule out the potential for ractopamine or zilpaterol to increase the risk of such events in individual cattle. The study was designed to investigate possible differences among treatment groups and between βAAs; it was not designed to determine arrhythmia rates or events that may be a risk factor for sudden death due to cardiac causes or other outcomes. Therefore, results should be interpreted accordingly.

In the study reported here, supplementation of feed with ractopamine and zilpaterol had no significant effects on arrhythmia rate or classification and blood lactate concentration in finishing steers. Both ractopamine and zilpaterol caused an increase in mean heart rate, with the greatest magnitude evident on day 7, after which it decreased throughout the remainder of the feeding period. Mean heart rate was within reference limits for all steers, except for those in the ractopamine group in day 1. Blood creatine kinase concentration was higher in the zilpaterol group than in the other groups on days 13 and 23. Additional research is needed regarding whether βAA use is a factor that may interact with cardiovascular, environmental, and management conditions to influence death rates in cattle during the late feeding period.

Acknowledgments

This manuscript represents a portion of a thesis submitted by Dr. Frese to the Kansas State University Department of Diagnostic Medicine and Pathobiology as partial fulfillment of the requirements for a Doctor of Philosophy degree.

Supported by the Beef Councils of California, Colorado, Idaho, Iowa, Kansas, Nebraska, and Oklahoma and the Beef Checkoff.

Dr. Loneragan has received consulting fees or honoraria from Elanco Animal Health, Merck Animal Health, and Zoetis.

ABBREVIATIONS

ADG

Average daily gain

βAA

β-adrenoceptor agonist

CI

Confidence interval

DM

Dry matter

SVPC

Supraventricular premature complex

VPC

Ventricular premature complex

Footnotes

a.

American Calan, Northwood, NH.

b.

Zilmax, Merck Animal Health, Summit, NJ.

c.

Optaflexx, Elanco Animal Health, Greenfield, Ind.

d.

Coviden Health Care Products, Dublin, Ireland.

e.

Greiner Bio One, Monroe, NC.

f.

ProCyte Dx, IDEXX Laboratories, Westbrook, Me.

g.

Nova CCX, Nova Biomedical, Waltham, Mass.

h.

Cobas c501, Roche Diagnostics, Indianapolis, Ind.

i.

Advia 2120i, Siemens Healthcare Diagnostics Inc, Tarrytown, NY.

j.

DR200/HE, NorthEast Monitoring Inc, Maynard, Mass.

k.

Invivo Quadtrode CV, Philips Medical Systems, Orlando, Fla.

l.

Luberex, GE Electronics, Rockford, Ill.

m.

Johnson & Johnson, New Brunswick, NJ.

n.

Holter LX analysis software, version 5.4, NorthEast Monitoring Inc, Maynard, Mass.

o.

ApopTag, Millipore, Temecula, Calif.

p.

SAS, version 9.3, SAS Institute, Cary, NC.

q.

Bednarski RM, McGuirk SM. Bradycardia associated with fasting in cattle (abstr). Vet Surg 1986;15:458.

References

  • 1. FDA. ZILMAX (zilpaterol hydrochloride): type A medicated article for cattle fed in confinement for slaughter. Freedom of Information summary original new animal drug application. NADA 141–258. Washington, DC: FDA, 2006.

    • Search Google Scholar
    • Export Citation
  • 2. FDA. Ractopamine hydrochloride: (OPTAFLEXX 45) type A medicated article for beef cattle. Freedom of Information summary original new animal drug application. NADA 141–221. Washington, DC: FDA, 2003.

    • Search Google Scholar
    • Export Citation
  • 3. Lean IJ, Thompson JM, Dunshea FR. A meta-analysis of zilpaterol and ractopamine effects on feedlot performance, carcass traits and shear strength of meat in cattle. PLoS ONE 2014;9:e115904.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Arp TS, Howard ST, Woerner DR, et al. Effects of dietary ractopamine hydrochloride and zilpaterol hydrochloride supplementation on performance, carcass traits, and carcass cutability in beef steers. J Anim Sci 2014;92:836843.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Scramlin SM, Platter WJ, Gomez RA, et al. Comparative effects of ractopamine hydrochloride and zilpaterol hydrochloride on growth performance, carcass traits, and longissimus tenderness of finishing steers. J Anim Sci 2010;88:18231829.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Mersmann HJ. Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci 1998;76:160172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Suissa S, Ernst P, Fau-Boivin JF, et al. A cohort analysis of excess mortality in asthma and the use of inhaled β-agonists. Am J Respir Crit Care Med 1994;149:604610.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Zaugg M, Xu WM, Lucchinetti E, et al. β-Adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation 2000;102:344350.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of β-agonists in patients with asthma and COPD: a meta-analysis. Chest 2004;125:23092321.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Burniston JG, Tan LB, Goldspink DF. β2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle. J Appl Physiol 2005;98:13791386.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Singh K, Xiao L, Remondino A, et al. Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol 2001;189:257265.

  • 12. Sears MR. Adverse effects of β-agonists. J Allergy Clin Immunol 2002;110:S322S328.

  • 13. Finn AF, Thompson CM, Banov CH, et al. β2-Agonist induced ventricular dysrhythmias secondary to hyperexcitable conduction system in the absence of a long QT syndrome. Ann Allergy Asthma Immunol 1997;78:230232.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Katz RW, Kelly HW, Crowley MR, et al. Safety of continuous nebulized albuterol for bronchospasm in infants and children. Pediatrics 1993;92:666669.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Yaeger MJ, Mullin K, Ensley SM, et al. Myocardial toxicity in a group of Greyhounds administered ractopamine. Vet Pathol 2012;49:569573.

  • 16. Loneragan GH, Thomson DU, Scott HM. Increased mortality in groups of cattle administered the β-adrenergic agonists ractopamine hydrochloride and zilpaterol hydrochloride. PLoS ONE 2014;9:e91177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Constable PD, Muir WW III, Bonagura JD, et al. Clinical and electrocardiographic characterization of cattle with atrial premature complexes. J Am Vet Med Assoc 1990;197:11631169.

    • Search Google Scholar
    • Export Citation
  • 18. McGuirk SM, Muir WW, Sams RA, et al. Atrial fibrillation in cows: clinical findings and therapeutic considerations. J Am Vet Med Assoc 1983;182:13801386.

    • Search Google Scholar
    • Export Citation
  • 19. Winterholler SJ, Parsons GL, Reinhardt CD, et al. Response to ractopamine-hydrogen chloride is similar in yearling steers across days on feed. J Anim Sci 2007;85:413419.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Elam NA, Vasconcelos JT, Hilton G, et al. Effect of zilpaterol hydrochloride duration of feeding on performance and carcass characteristics of feedlot cattle. J Anim Sci 2009;87:21332141.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Smith BP. Large animal internal medicine. St Louis: Mosby, 2002.

  • 22. Zimmerli UV, Blum JW. Acute and long-term metabolic, endocrine, respiratory, cardiac and skeletal-muscle activity changes in response to perorally administered β-adrenoceptor agonists in calves. J Anim Physiol Anim Nutr (Berl) 1990;63:157172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Eisemann JH, Bristol DG. Change in insulin sensitivity or responsiveness is not a major component of the mechanism of action of ractopamine in beef steers. J Nutr 1998;128:505511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Wagner SA, Mostrom MS, Hammer CJ, et al. Adverse effects of zilpaterol administration in horses: three cases. J Equine Vet Sci 2008;28:238243.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Hepworth-Warren KL, Alcott CJ. Treatment and resolution of zilpaterol hydrochloride toxicity in a Quarter Horse gelding. Equine Vet Educ 2014;26:8185.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Schmidt G, Morfill GE, Barthel P, et al. Variability of ventricular premature complexes and mortality risk. Pace-Pacing Clin Electrophysiol 1996;19:976980.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Sajadieh A, Nielsen OW, Rasmussen V, et al. Ventricular arrhythmias and risk of death and acute myocardial infarction in apparently healthy subjects of age ≥ 55 years. Am J Cardiol 2006;97:13511357.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Burrin DG, Britton RA. Response to monensin in cattle during subacute acidosis. J Anim Sci 1986;63:888893.

  • 29. Novak LP, Tillery GW. Relationship of serum creatine phosphokinase to body composition. Hum Biol 1977;49:375380.

  • 30. Garcia W. Elevated creatine-phosphokinase levels associated with large muscle mass: another pitfall in evaluating clinical significance of total serum CPK activity. JAMA 1974;228:13951396.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Avendaño-Reyes L, Torres-Rodríguez V, Meraz-Murillo FJ, et al. Effects of two β-adrenergic agonists on finishing performance, carcass characteristics, and meat quality of feedlot steers. J Anim Sci 2006;84:32593265.

    • Crossref
    • Search Google Scholar
    • Export Citation

Appendix

Composition of an experimental diet* fed to finishing steers.

ComponentValue
Ingredient (percentage of DM)
   Corn grain (cracked)58.5
   Dried distiller's grains plus solubles21.5
   Cottonseed hulls12.3
   Molasses (cane)2.5
   Supplement pellet†5.2
Chemical composition (DM basis)‡ 
   DM (%)86.5
   Crude protein (%)13.5
   Net energy for maintenance (Mcal/kg)2.12
   Net energy for gain (Mcal/kg)1.45
   Calcium (%)0.79
   Phosphorus (%)0.48
   Salt (%)0.79

To manufacture the other 2 diets used in the study, type B articles were added to result in diets containing zilpaterol hydrochloride (8.3 mg/kg [3.8 mg/lb] on a DM basis) or ractopamine hydrochloride (300 mg in 7.25 kg [16 lb] on an as-fed basis or 46 mg/kg (20.9 mg/lb) on a DM basis). †Pellet formulated to contain the following ingredients (as-fed basis): crude protein, 14.75%; calcium, 12.0%; phosphorus, none added; potassium, 1.0%; magnesium, 1.4%; salt, 5.25%; vitamin A, 88,000 U/kg (40,000 U/lb); vitamin D, 8,800 U/kg (4,000 U/lb); vitamin E, 176 U/kg (80.0 U/lb); thiamine, 352 U/kg (160.0 U/lb); copper, 212 ppm; zinc, 635 ppm; monensin, 617 mg/kg (280.5 mg/lb); and tylosin, 159 mg/kg (72.3 mg/lb). ‡Analyzed by Servi-Tech Laboratories, Hastings, Neb.

  • Figure 1—

    Photograph showing a steer fitted with a Holter monitor and harness.

  • 1. FDA. ZILMAX (zilpaterol hydrochloride): type A medicated article for cattle fed in confinement for slaughter. Freedom of Information summary original new animal drug application. NADA 141–258. Washington, DC: FDA, 2006.

    • Search Google Scholar
    • Export Citation
  • 2. FDA. Ractopamine hydrochloride: (OPTAFLEXX 45) type A medicated article for beef cattle. Freedom of Information summary original new animal drug application. NADA 141–221. Washington, DC: FDA, 2003.

    • Search Google Scholar
    • Export Citation
  • 3. Lean IJ, Thompson JM, Dunshea FR. A meta-analysis of zilpaterol and ractopamine effects on feedlot performance, carcass traits and shear strength of meat in cattle. PLoS ONE 2014;9:e115904.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Arp TS, Howard ST, Woerner DR, et al. Effects of dietary ractopamine hydrochloride and zilpaterol hydrochloride supplementation on performance, carcass traits, and carcass cutability in beef steers. J Anim Sci 2014;92:836843.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Scramlin SM, Platter WJ, Gomez RA, et al. Comparative effects of ractopamine hydrochloride and zilpaterol hydrochloride on growth performance, carcass traits, and longissimus tenderness of finishing steers. J Anim Sci 2010;88:18231829.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Mersmann HJ. Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci 1998;76:160172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Suissa S, Ernst P, Fau-Boivin JF, et al. A cohort analysis of excess mortality in asthma and the use of inhaled β-agonists. Am J Respir Crit Care Med 1994;149:604610.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Zaugg M, Xu WM, Lucchinetti E, et al. β-Adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation 2000;102:344350.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of β-agonists in patients with asthma and COPD: a meta-analysis. Chest 2004;125:23092321.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Burniston JG, Tan LB, Goldspink DF. β2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle. J Appl Physiol 2005;98:13791386.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Singh K, Xiao L, Remondino A, et al. Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol 2001;189:257265.

  • 12. Sears MR. Adverse effects of β-agonists. J Allergy Clin Immunol 2002;110:S322S328.

  • 13. Finn AF, Thompson CM, Banov CH, et al. β2-Agonist induced ventricular dysrhythmias secondary to hyperexcitable conduction system in the absence of a long QT syndrome. Ann Allergy Asthma Immunol 1997;78:230232.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Katz RW, Kelly HW, Crowley MR, et al. Safety of continuous nebulized albuterol for bronchospasm in infants and children. Pediatrics 1993;92:666669.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Yaeger MJ, Mullin K, Ensley SM, et al. Myocardial toxicity in a group of Greyhounds administered ractopamine. Vet Pathol 2012;49:569573.

  • 16. Loneragan GH, Thomson DU, Scott HM. Increased mortality in groups of cattle administered the β-adrenergic agonists ractopamine hydrochloride and zilpaterol hydrochloride. PLoS ONE 2014;9:e91177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Constable PD, Muir WW III, Bonagura JD, et al. Clinical and electrocardiographic characterization of cattle with atrial premature complexes. J Am Vet Med Assoc 1990;197:11631169.

    • Search Google Scholar
    • Export Citation
  • 18. McGuirk SM, Muir WW, Sams RA, et al. Atrial fibrillation in cows: clinical findings and therapeutic considerations. J Am Vet Med Assoc 1983;182:13801386.

    • Search Google Scholar
    • Export Citation
  • 19. Winterholler SJ, Parsons GL, Reinhardt CD, et al. Response to ractopamine-hydrogen chloride is similar in yearling steers across days on feed. J Anim Sci 2007;85:413419.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Elam NA, Vasconcelos JT, Hilton G, et al. Effect of zilpaterol hydrochloride duration of feeding on performance and carcass characteristics of feedlot cattle. J Anim Sci 2009;87:21332141.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Smith BP. Large animal internal medicine. St Louis: Mosby, 2002.

  • 22. Zimmerli UV, Blum JW. Acute and long-term metabolic, endocrine, respiratory, cardiac and skeletal-muscle activity changes in response to perorally administered β-adrenoceptor agonists in calves. J Anim Physiol Anim Nutr (Berl) 1990;63:157172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Eisemann JH, Bristol DG. Change in insulin sensitivity or responsiveness is not a major component of the mechanism of action of ractopamine in beef steers. J Nutr 1998;128:505511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Wagner SA, Mostrom MS, Hammer CJ, et al. Adverse effects of zilpaterol administration in horses: three cases. J Equine Vet Sci 2008;28:238243.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Hepworth-Warren KL, Alcott CJ. Treatment and resolution of zilpaterol hydrochloride toxicity in a Quarter Horse gelding. Equine Vet Educ 2014;26:8185.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Schmidt G, Morfill GE, Barthel P, et al. Variability of ventricular premature complexes and mortality risk. Pace-Pacing Clin Electrophysiol 1996;19:976980.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Sajadieh A, Nielsen OW, Rasmussen V, et al. Ventricular arrhythmias and risk of death and acute myocardial infarction in apparently healthy subjects of age ≥ 55 years. Am J Cardiol 2006;97:13511357.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Burrin DG, Britton RA. Response to monensin in cattle during subacute acidosis. J Anim Sci 1986;63:888893.

  • 29. Novak LP, Tillery GW. Relationship of serum creatine phosphokinase to body composition. Hum Biol 1977;49:375380.

  • 30. Garcia W. Elevated creatine-phosphokinase levels associated with large muscle mass: another pitfall in evaluating clinical significance of total serum CPK activity. JAMA 1974;228:13951396.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Avendaño-Reyes L, Torres-Rodríguez V, Meraz-Murillo FJ, et al. Effects of two β-adrenergic agonists on finishing performance, carcass characteristics, and meat quality of feedlot steers. J Anim Sci 2006;84:32593265.

    • Crossref
    • Search Google Scholar
    • Export Citation

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